Salt-sensitive hypertension in ANP knockout mice: potential role of abnormal plasma renin activity.
Atrial natriuretic peptide (ANP), a peptide hormone produced by the heart, exerts a chronic hypotensive effect. Knockout mice with a homozygous disruption of the pro-ANP gene (-/-) are incapable of producing ANP and are hypertensive relative to their wild-type (+/+) siblings. Previous studies showed that arterial blood pressure (ABP) was further increased in conscious -/- mice kept for 2 wk on 2% salt, but not in anesthetized -/- mice after 1 wk on 8% salt. To determine whether inconsistencies in observed effects of salt on ABP of -/- mice are due to duration of increased salt intake and/or the state of consciousness of the animals, we measured ABP from an exteriorized carotid catheter during and after recovery from anesthesia with ketamine-xylazine in adult +/+ and -/- mice kept on low (LS; 0.008% NaCl)- or high (HS; 8% NaCl)-salt diets for 3-4 wk. Conscious ABP +/- SE (mmHg) of +/+ mice did not differ significantly on either diet (HS, 113 +/- 3; LS, 110 +/- 5). However, on HS diet -/- mice had significantly higher ABP (135 +/- 3; P < 0.001) than both -/- (115 +/- 2) and +/+ (110 +/- 5) mice on LS diet. Anesthesia decreased ABP in all groups, but the the genotype- and diet-related differences were preserved. Plasma renin activity (PRA, ng ANG I.ml-1.h-1) in blood collected at termination of experiment was appropriately different on the 2 diets in +/+ mice (HS, 4.9 +/- 1.9; LS, 21 +/- 2.8). However, PRA failed to decrease in -/- mice on HS diet (HS, 18 +/- 2.9; LS, 19 +/- 3.7). Independent of genotype, concentration of endothelin-1 (ET-1, pg/mg protein) and endothelial constitutive NOS (ecNOS, density/100 micrograms protein) was significantly elevated in kidneys of mice fed on HS diet (ET-1 -/-, 31 +/- 4.7 and +/+, 32 +/- 4.1; ecNOS -/-, 160 +/- 19 and +/+, 156 +/- 19) compared with mice fed on LS diet (ET-1 -/-, 19 +/- 1.9 and +/+, 21 +/- 1.8; ecNOS -/-, 109 +/- 13 and +/+, 112 +/- 18). We conclude that, regardless of the state of alertness, -/- mice develop salt-sensitive hypertension after prolonged feeding on HS, in part due to their inability to reduce PRA, whereas the specific renal upregulation of ecNOS and ET-1 in response to HS intake may be an ANP-independent adaptive adjustment aimed at improving kidney function and counteracting the pressor effect of salt.
Melo
L G
LG
Department of Physiology, University of Toronto, Ontario, Canada.
Veress
A T
AT
Chong
C K
CK
Pang
S C
SC
Flynn
T G
TG
Sonnenberg
H
H
D000704:Analysis of Variance; D000803:Angiotensin I / Q000097:blood; D000818:Animals; D009320:Atrial Natriuretic Factor / Q000172:deficiency* / Q000235:genetics / Q000502:physiology*; D001794:Blood Pressure; D004039:Diet, Sodium-Restricted; D019332:Endothelin-1 / Q000096:biosynthesis; D005091:Exons; D005260:Female; D006579:Heterozygote; D006720:Homozygote; D006973:Hypertension / Q000097:blood / Q000235:genetics / Q000503:physiopathology*; D007668:Kidney / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009206:Myocardium / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000096:biosynthesis; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; D011498:Protein Precursors / Q000172:deficiency / Q000235:genetics; D012083:Renin / Q000097:blood*; D012982:Sodium, Dietary
D019332:Endothelin-1; D011498:Protein Precursors; D012982:Sodium, Dietary; D009320:Atrial Natriuretic Factor; D000803:Angiotensin I; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; C496315:Nos3 protein, mouse; D012083:Renin